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- Effects of tenofovir disoproxil fumarate on intrahepatic viral burden and liver immune microenvironment in patients with chronic hepatitis B
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Original research
Effects of tenofovir disoproxil fumarate on intrahepatic viral burden and liver immune microenvironment in patients with chronic hepatitis B
- David Z Pan1,
- Cameron M Soulette1,
- Abhishek Aggarwal1,
- Dong Han1,
- Nicholas van Buuren1,
- Peiwen Wu1,
- Becket Feierbach1,
- http://orcid.org/0000-0001-9368-6141Jaw-Town Lin2,
- Cheng-Hao Tseng3,
- Chi-Yi Chen4,
- Bryan Downie1,
- Hongmei Mo1,
- Lauri Diehl1,
- Li Li1,
- Simon P Fletcher1,
- Scott Balsitis1,
- http://orcid.org/0000-0003-1668-6230Ricardo Ramirez1,
- Vithika Suri1,
- http://orcid.org/0000-0001-8984-5103Yao-Chun Hsu2,5
- 1Gilead Sciences Inc, Foster City, California, USA
- 2Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
- 3Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Cancer Hospital, I-Shou University, Kaohsiung, Taiwan
- 4Department of Internal Medicine, Chiayi Christian Hospital, Chia-Yi, Taiwan
- 5Graduate Institute of Medicine, Colleage of Medicine, I-Shou University, Kaohsiung, Taiwan
- Correspondence to Professor Yao-Chun Hsu; holdenhsu{at}ntu.edu.tw
Abstract
Background The impact of nucleos(t)ide analogues on intrahepatic viral burden and immune microenvironment in patients with chronic hepatitis B (CHB) is not clear.
Objective We aimed to characterise the effects of tenofovir disoproxil fumarate (TDF) on intrahepatic viral burden and the liver immune microenvironment in patients with CHB.
Design Core liver biopsies were collected at baseline and year 3 from patients with CHB with minimally raised serum alanine aminotransferase in a double-blind placebo-controlled trial (NCT01522625). Paired biopsies were analysed by RNA-sequencing (n=119 pairs), a custom multiplex immunofluorescence assay (n=30 pairs), and HBV-targeted long-read DNA sequencing (n=49 pairs).
Results Both non-integrated and integrated HBV DNA were present in all patients at baseline, with >65% having interchromosomal translocations. Treatment significantly reduced the frequency of HBV core+ hepatocytes and intrahepatic (integrated and non-integrated) HBV DNA, but had no effect on HBsAg+ hepatocytes. Clonally expanded integrations were enriched for HBsAg coding regions and showed dysregulation of nearby genes. At baseline, there was significant enrichment of intrahepatic CD8+ T cell proximity to HBV core+ hepatocytes, but not to HBsAg+ cells. The densities of T cells and B cells were significantly reduced by TDF. Transcriptomic analyses found TDF induced widespread downregulation of immune-related genes including inhibitory and regulatory genes.
Conclusion TDF significantly reduced intrahepatic integrated and non-integrated HBV DNA, exerting disparate effects on HBV core+ and HBsAg+ cells and on different immune cell subsets. Our data suggest there may be differential cytotoxic T cell-mediated killing of HBV core+ versus HBsAg+ hepatocytes, providing insights for HBV cure strategies.
- hepatitis B
- antiviral therapy
Data availability statement
Data are available upon reasonable request. Data collected for this study, including deidentified individual participant data and data dictionaries defining fields in the datasets, will be made available on request to with qualified external researchers based on submitted curriculum vitae and reflecting non conflict of interest as well as laws and regulations regarding patient privacy. Approval of such requests is dependent on the nature of the request, the merit of the research proposed, the availability of the data and the intended use of the data. Data requests should be sent to the corresponding author at holdenhsu@gmail.com.
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- hepatitis B
- antiviral therapy
Data availability statement
Data are available upon reasonable request. Data collected for this study, including deidentified individual participant data and data dictionaries defining fields in the datasets, will be made available on request to with qualified external researchers based on submitted curriculum vitae and reflecting non conflict of interest as well as laws and regulations regarding patient privacy. Approval of such requests is dependent on the nature of the request, the merit of the research proposed, the availability of the data and the intended use of the data. Data requests should be sent to the corresponding author at holdenhsu@gmail.com.
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Footnotes
DZP, CMS and AA are joint first authors.
DZP, CMS and AA contributed equally.
Contributors DZP, CMS, AA, NvB, BF and VS conceived and designed the study. NvB coordinated sample inventories and databases. AA, DH, NvB and RR designed and performed the experiments. DZP, CMS, AA, PW and RR analysed the data. DZP, CMS, AA, RR, SPF and SB wrote the manuscript. BD, HM, LD, LL SPF, SB, VS and Y-CH supervised the study and reviewed the manuscript. J-TL, C-HT and Y-CH coordinated the clinical trial and biopsy collection. Y-CH is the guarantor of the study.
Funding This work was funded by Gilead Sciences Inc. Yao-Chun Hsu was supported by the National Science and Technology Council in Taiwan (112-2314-B-214 -005 -MY3 and 110-2314-B-214 -006 -MY3).
Competing interests DZP, CMS, AA, DH, NvB, PW, BF, BD, LL, LD, HM, SPF, SB, RR and VS were employees and stockholders of Gilead Sciences, Inc. J-TL, C-HT and Y-CH have research support from Gilead Sciences. C-HT and Y-CH are paid lecturers for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp & Dohme and Novartis. Y-CH is an advisory committee member for Gilead Sciences.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
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